The following includes information that may be useful in understanding the present invention. It is not an admission that any of the information, publications or documents specifically or implicitly referenced herein is prior art, or essential, to the presently described or claimed inventions. All publications and patents mentioned herein are hereby incorporated herein by reference in their entirety.
Heart disease, including ischemic heart disease, myocardial infarctions and other acute coronary syndromes, as well as heart failure, is a major health problem throughout the world.
It is understood, for example, that myocardial infarctions are a significant source of mortality among those individuals with heart disease. Myocardial infarction (MI) or acute myocardial infarction (AMI), commonly known as a heart attack, is the interruption of blood supply to a part of the heart, causing heart cells to die. This is most commonly due to occlusion (blockage) of a coronary artery following the rupture of a vulnerable atherosclerotic plaque, which is an unstable collection of lipids and white blood cells (especially macrophages) in the wall of an artery. The resulting ischemia and oxygen shortage, if left untreated for a sufficient period of time, can cause damage or death (infarction) of heart muscle tissue, i.e., the myocardium. Classical symptoms of acute myocardial infarction include sudden chest pain (typically radiating to the left arm or left side of the neck), shortness of breath, nausea, vomiting, palpitations, sweating, and anxiety. Approximately one quarter of all myocardial infarctions, however, are “silent,” i.e., without chest pain or other symptoms. Immediate treatment for suspected acute myocardial infarction includes oxygen, aspirin, and sublingual nitroglycerin. Most cases of ST elevation MI (STEMI, also sometimes referred to as transmural myocardial infarction, or Q-wave myocardial infarction) are treated with thrombolysis or percutaneous coronary intervention (PCI). NSTEMI (non-ST elevation MI, also sometimes referred to as nontransmural myocardial infarction, or non-Q-wave myocardial infarction) is managed with medication, although PCI is often performed during hospital admission. Heart attacks are the leading cause of death for both men and women worldwide.
Heart failure (HF), often called congestive heart failure (CHF), is a clinical syndrome characterized by systemic perfusion inadequate to meet the body's metabolic demands as a result of impaired cardiac pump function, i.e., it is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure is a common, costly, disabling, and potentially deadly condition. McMurray J J, Pfeffer M A (2005) “Heart failure”. Lancet 365 (9474): 1877-89. In developed countries, around 2% of adults suffer from heart failure, but in those over the age of 65, this increases to 6-10%. Id. Currently, it is estimated that more than 5 million Americans are afflicted with heart failure, approximately 2% of the population. American Heart Association. Heart Disease and Stroke Statistics—2008 Update. Dallas: American Heart Association, 2008. Both the human suffering and the financial burden associated with HF are substantial. Patients with heart failure account for about 1 million hospital admissions annually, and another 2 million patients have heart failure as a secondary diagnosis. One third of these patients are readmitted within 90 days for recurrent decompensation. Common causes of heart failure include myocardial infarction and other forms of ischemic heart disease, hypertension, valvular heart disease, and cardiomyopathy. McMurray J J, Pfeffer M A (2005) “Heart failure”. Lancet 365 (9474): 1877-89.
Heart failure may be further subdivided into systolic or diastolic heart failure. In systolic heart failure, there is reduced cardiac contractility, whereas in diastolic heart failure there is impaired cardiac relaxation and abnormal ventricular filling. The most common cause of heart failure is left ventricular (LV) systolic dysfunction (about 60% of patients). In this category, most cases are a result of end-stage coronary artery disease, either with a history of myocardial infarction or with a chronically underperfused, yet viable, myocardium. In many patients, both processes are present simultaneously. Other common causes of LV systolic dysfunction include idiopathic dilated cardiomyopathy, valvular heart disease, hypertensive heart disease, toxin-induced cardiomyopathies (e.g., doxorubicin, herceptin, alcohol), and congenital heart disease. Heart failure can also develop as a result of right ventricular infarction, pulmonary hypertension, chronic severe tricuspid regurgitation, or arrhythmogenic right ventricular dysplasia. A less-common cause of heart failure is high-output failure caused by thyrotoxicosis, arteriovenous fistulae, Paget's disease, pregnancy, or severe chronic anemia. Diastolic LV dysfunction (impaired relaxation) usually is related to chronic hypertension or ischemic heart disease. Other causes include restrictive, infiltrative, and hypertrophic cardiomyopathies. Inadequate filling of the right ventricle can result from pericardial constriction or cardiac tamponade. Patients at high risk for developing heart failure are those with hypertension, coronary artery disease, diabetes mellitus, family history of cardiomyopathy, use of cardiotoxins, and obesity. Heart failure is a common syndrome, especially in older adults. Although more patients survive acute myocardial infarction because of reperfusion therapy, most have at least some residual LV systolic dysfunction, which can lead to heart failure. Currently, heart failure has no cure. While treatments such as medicines and lifestyle changes can help people live longer and more active lives, researchers continue to look for new ways to treat heart failure and its complications.
Chest pain is a nonspecific symptom that can have cardiac causes, and the term angina is typically reserved for pain syndromes arising from presumed myocardial ischemia. The term unstable angina was first used to signify the intermediate state between myocardial infarction and the more chronic state of stable angina. The old term, preinfarction angina, conveys the clinical intent of intervening to attenuate the risk of myocardial infarction or death. Patients with this condition have also been categorized according to their presentation, diagnostic test results, or course over time; these categories include new-onset angina, accelerating angina, rest angina, early postinfarct angina, and early postrevascularization angina. Unstable angina is considered to be an acute coronary syndrome in which there is no release of the enzymes and biomarkers of myocardial necrosis. Although the etiology and definition of unstable angina can be broad, interplay between disrupted atherosclerotic plaque and overlaid thrombi is present in many cases of unstable angina, with consequent hemodynamic deficit or microembolization. This is distinct from stable angina, in which the typical underlying cause is a fixed coronary stenosis with compromised blood flow and slow, progressive plaque growth that allows for the occasional development of collateral flow.
“Acute Coronary Syndrome” (ACS) has been applied to a group of coronary disorders that result from ischemic insult to the heart. ACS includes patients who have or are at high risk of developing an MI. Patients with ACS present to the physician with conditions that span a continuum that includes unstable angina, STEMI, NSTEMI and transmural (Q-wave) MI. ACS also include cardiac ischemia, and is believed to result largely from thrombus deposition and growth within one or more coronary arteries, resulting in a partial or complete occlusion of the artery, and frequently involves rupture of the plaque, resulting in an ischemic injury. ACS may also be precipitated by a coronary vasospasm or increased myocardial demand. For review, see, e.g., Davies, Clin. Cardiol. (Supp. I): 12 17 (1997). The seriousness of ACS is underlined by the morbidity and mortality that follow the ischemic insult. For example, workers have estimated that within four to six weeks of presentation with ACS, the risk of death or a subsequent MI is 8-14%, and the rate of death, MI, or refractory ischemia is 15-25%. Theroux and Fuster, Circulation 97:1195 1206 (1998). Given that the total number of deaths in the U.S. from acute MI is about 600,000, the search within the art for information that relates to the therapeutic management of ACS has understandably been extensive.
B-type natriuretic peptide (BNP or BNP-32) is a 32-amino acid neurohormone that is synthesized in ventricular myocardium and released into the circulation in response to ventricular dilation and pressure overload. The plasma concentration of BNP is elevated among CHR patients, and increases in proportion to the degree of left ventricular dysfunction and the severity of CHF symptoms. For review, see, e.g., Wiese et al., Circulation 102: 3074 9 (2000); Yasue et al., Circulation 90: 195 203 (1994); Yoshimura et al., Circulation 87: 464 9 (1993); Stein and Levin, Am. Heart J. 135: 914 23 (1998); and Omland et al., Heart 76: 232 7 (1996). The precursor to BNP is synthesized as a 134-amino acid precursor molecule referred to as “pre pro BNP,” which is cleaved into a signal peptide comprising amino acids 1-26 and a 108-amino acid molecule consisting of amino acids 27-134, referred to as “pro BNP.” Pro BNP is proteolytically processed into a 76-amino acid N-terminal peptide (amino acids 1-76), referred to as “NT pro BNP” and the 32-amino acid mature hormone, referred to as BNP or BNP 32 (amino acids 77-108). It has been reported that NT pro-BNP, BNP-32, and the pre pro BNP can circulate in human plasma. See, e.g., Tateyama et al., Biochem. Biophys. Res. Commun. 185: 760 7 (1992); Hunt et al., Biochem. Biophys. Res. Commun. 214: 1175 83 (1995).
In August 2001, hBNP (native peptide) was approved by the FDA under the trade name Natrecor (nesiritide) for the treatment of acute congestive heart failure. Natrecor was the first drug approved for the treatment of CHF in over twelve years. It is administered by intravenous continuous infusion over a period of 48 hours in patients with acute decompensated or advanced CHF who have dyspnea at rest or with minimal activity. As the drug is expensive and requires hospitalization, Natrecor is only used for the most acute cases. Additionally, the therapeutic usefulness of BNP is limited by endopeptidase degradation, as well as natriuretic peptide clearance receptor (NPR-C) mediated internalization, which causes these proteins to have a fairly short half-life in vivo. For example, the plasma half life of BNP is estimated to be approximately 20 minutes (Potter et al., Endocrine Reviews 27(1):42-72 (2006)), and previous therapeutic administration of these peptides has been limited to time consuming intravenous infusion, typically in a hospital or other medical care facility.
There remains a need in the art for new therapeutics useful in treating patients having or at risk for developing cardiovascular diseases, disorders and conditions, including ischemic heart disease, acute coronary syndromes and heart failure. There is a particular need for new therapeutics that span the entire spectrum of cardiovascular diseases, disorders and conditions associated with ischemia and/or oxidative stress. Such therapeutics are described and claimed herein, based on surprising discoveries indicating, for example, that signal peptide fragments of BNP are novel cardioprotective and therapeutic agents.